tbuckley/cabot-search huggingface dataset:
P05.02.A PRELIMINARY FINDINGS FROM THE MRI QUALITY ASSURANCE PROGRAMME FOR THE PROSPECTIVE MULTI-SITE AUSTRALIAN FIG ([FET-PET IN GLIOBLASTOMA) TROG 18.06 STUDY
Authors: C Brighi, B A Moffat, A Whitehead, O Cook, A Moore, A Grose, A Rossi, R Dykyj, E Lau, G Fitt, A Lasocki, H K Gan, A M Scott, E Koh
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The O-(2-[18F]-fluoroethyl)-L-tyrosine positron emission tomography (FET-PET) in Glioblastoma (FIG) study is a prospective study evaluating the management impact of FET-PET imaging in up to 210 newly diagnosed adult glioblastoma patients across 10 Australian sites. Patients undergo contrast MRI and FET-PET at 3 timepoints: pre-chemoradiotherapy (CRT), one-month post-CRT and at suspected progression. MRI QA programme components, approach and integrated workflows are described here. MATERIAL AND METHODS The FIG MRI protocol comprised 3D-T1, 3D-FLAIR, Axial 2D DWI (including derived ADC map), DCE (including T1 mapping), DSC, Axial T2 and 3D T1-post-contrast (T1C) sequences, with SWI and 3D DIR sequences optional. QA components included data acquisition quality and completeness (standard and advanced), motion artefact, low contrast to noise or signal to noise, series description and susceptibility artifacts. Suitability of T1/T1C using modified RANO (mRANO) criteria was assessed. An optimised workflow involved site upload from local PACS systems to centralised database via TROG Central Quality Management System (CQMS) platform and collation into a central imaging database utilising MIM software. The MRI QA workflow encompassed automated anonymisation of DICOM data, data completeness and reconstruction evaluation, then review by two expert neuroimaging analysts. Sites received feedback with request for resubmission where required. RESULTS Between December 2021 and February 2023, MRI data in 74 patients across 9 sites with median of 6 patients (range 2-17) per site was submitted. A total of 141 MRI datasets across all timepoints were collected (per site range:4-35, median:13), with 43 imaging time-points selected for QA (per site range:3-12, median: 4). Importantly, 41/43 (95%) of initial datasets were deemed suitable for mRANO assessment, but only 13/43 (30%) were suitable for advanced MRI analysis. Very few datasets had motion or susceptibility artifacts, low contrast to noise or signal to noise, or incorrect series description. Technical issues identified included incomplete data (DCE - missing T1 maps, DWI - missing ADC maps), incorrect sequence reconstruction (DCE split series and Axial/Sagittal/Coronal reformats for 3D images) and lack of non-mandatory SWI sequences. Feedback to sites resulted in improvements in DCE sequence acquisition from split series in 11/45 (24%) to preferred single series in 18/24 (75%) and similar increases in T1 maps completeness from 7/19 (37%) to 7/7 (100%). CONCLUSION Despite challenges in multisite workflow and substantial multi-modality site and central data management, a robust MRI QA program has confirmed 95% compliance for mRANO assessment. Site specific feedback resulted in increased compliance with advanced MRI sequences to enable detailed future analysis.
P03.11.B MITOTIC ENRICHMENT AS AN EFFICIENT RADIOSENSITIZATION STRATEGY FOR INTRACRANIAL TUMORS
Authors: M C de Gooijer, H Çolakoğlu, C H Çitirikkaya, D M Fedorushkova, A El Ouazani, R Shah, M H Meel, E Hulleman, G R Borst, O van Tellingen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Radiotherapy remains one of the most effective modalities for anticancer treatment and part of standard of care for many primary and metastatic brain tumors. Boosting the efficacy of radiotherapy is therefore a logical avenue to improve patient survival. We have developed a radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied fractionated radiotherapy regimens. MATERIAL AND METHODS Mitotic enrichment in vitro is established using flow cytometry and radiosensitization is assessed using colony formation assays. In vivo, several independent luciferase-tagged orthotopic brain tumor models are used to investigate mitotic enrichment (phospho-histone 3 immunohistochemistry), tumor growth, survival and healthy tissue toxicity (body weight, blood liver enzymes, γH2AX and cleaved-caspase 3 immunohistochemistry). Pharmacokinetic studies are quantified using LC-MS/MS. All experiments on primary brain tumors included serum-free neurosphere culture models. RESULTS We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. This tubulin inhibitor (ABT-751) efficiently radiosensitizes a range of preclinical tumor models representing adult and pediatric, primary and metastatic brain tumors. Importantly, ABT-751 also improves survival in mouse models of adult glioblastoma (GBM), but only in a mitotic enrichment setup when given several hours prior to radiotherapy to allow accumulation in mitosis. Of note, induction of mitotic enrichment does not exacerbate healthy tissue toxicity. CONCLUSION Induction of mitotic enrichment by ABT-751 radiosensitizes adult GBM to fractionated radiotherapy. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other targets and cancers and have designed a phase 0/I trial for adult GBM to demonstrate induction of mitotic enrichment and tolerability when combined with radiotherapy. We expect to start enrollment in this trial soon.
P15.17.B DYNAMIC FDG PET AS A PREDICTOR OF SURVIVAL IN PATIENTS WITH GLIOMAS
Authors: S Moosa, P Ramanathan, Z Qureshi, B Kundu, M Quigg
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The neuroimaging characteristics of treatment-related necrosis (TRN) induced by chemotherapy and radiotherapy mimic those of tumor progression (TPR). This can make it challenging for clinicians to deliver prognoses for patients with gliomas and subsequently optimize their treatment regimens. In this study, we evaluate the utility of dynamic FDG (dFDG) PET, which provides information about dynamic metabolic changes, for predicting survival in patients who have undergone treatment for gliomas. MATERIAL AND METHODS Clinical and radiographic information were obtained for 21 adult patients with known or suspected recurrent gliomas and had radiographic worsening reported on MRI within 6 months of completion of radiation and chemotherapy. All patients underwent dFDG PET imaging, and the prognostic significance of rate constants from the suspected tumor region were analyzed using Cox regressions. RESULTS Based on dFDG PET imaging, higher values of the k3 rate constant predicted a hazard ratio of 6.7 of death within 12 months of diagnosis. Hazard ratios of the k1 and k2 parameters were not significant in prediction of 12-month survival. CONCLUSION The k3 kinetic parameter of dFDG PET imaging, a marker for glucose uptake and metabolism, is predictive of 12-month survival in glioma patients who have questionable tumor progression. Clinicians can use this information to estimate the likelihood of TPR versus TRN in patients with gliomas and subsequently tailor their treatment plans based upon expected survival.
P09.12.B EFFECT OF TRADITIONAL CHINESE MEDICINE (TCM) AND WESTERN NATUROPATHY ON PATIENTS WITH GLIOBLASTOMA
Authors: R Goldbrunner, S Roth-Goldbrunner, M Timmer, C Nettekoven, S Kochs
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND IDH wildtype Glioblastoma (GBM) is an aggressive brain tumor with dismal prognosis. Current efforts focus on integration of supportive therapies like psychooncology and palliative care in routine care. Traditional Chinese Medicine (TCM) and western naturopathy are integrative modalities that have been studied recently for managing various symptoms and diseases. Aim of this study was to assess effects of TCM and western naturopathy on symptom burden relief and survival of glioblastoma patients. METHODS In this retrospective study we performed a matched pair analysis comparing 21 GBM patients with a combined treatment comprising standard radio chemotherapy plus TCM and western naturopathy (TCM group) with matched control patients receiving standard radiochemotherapy alone (control group). Matching was done according to age, gender, IDH status, MGMT methylation status and KPS. Statistical analysis was performed using GraphPad Prism 9. RESULTS The patient in the TCM group felt better regarding their general condition and had less symptom burden. Moreover, progression free survival (PFS) was significantly longer in the TCM group (17.4 +/- 12.2 months) compared to the control group (12.6 +/- 6.9 months; p &amp;lt; 0.01). Overall survival increased from 20.5 +/- 8.5 (control group) to 25.0 +/- 14.5 months (TCM group, n.s.). CONCLUSION Glioblastoma patients seem to benefit significantly from additional integrative medicine including TCM and western naturopathy , both, in terms of symptom relieve and regarding progression free survival. However, a prospective randomized trial with a larger patient cohort would be necessary in order to confirm this effect.
P08.09.B EFFECTS OF A ONE-WEEK SKIING INTERVENTION ON LOWER LIMB MUSCLE STRENGTH IN BRAIN TUMOR PATIENTS AND THEIR CAREGIVERS
Authors: J Jost, N Hansel, R Brandt, L Lemcke, W Stummer, R G Wiewrodt, D Wiewrodt
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Due to fatigue or feelings of insecurity, many brain tumor patients are not sufficiently active. Among other things, this puts patients at higher risk for sarcopenia predicting overall survival. Exercise interventions of various kinds could effectively counteract this problem. Here, we aim to present the impact of a one-week skiing intervention on leg muscle strength in brain tumor patients and their caregivers as well as feasibility and safety of the intervention. MATERIAL AND METHODS Ten brain tumor patients and their families participated in this one-week skiing intervention in a self-catering lodge at 1400m altitude. Daily 4-hour ski sessions (including approx. 1 hour rest) with professional ski instructors were performed in small groups (≤5 participants) divided by proficiency level. Participants could choose between downhill and cross-country skiing. Adverse events were noted daily. Muscle strength was determined 3-10 days pre- and postintervention on 5 different gym machines (knee extension, knee flexion, adductors, abductors, leg press) using Brzycki's equation. RESULTS 20 adults (10 patients, 10 caregivers) and 7 children participated in the ski-based intervention. All patients were surgically treated at least once and received chemo- and/or radiotherapy (ongoing chemotherapy in 6 patients). No severe adverse events were recorded throughout the week. 15 adults (9 patients, 56% female; 6 caregivers, 67% female) aged 21-69 years (mean 50 years) completed the muscle strength tests. Of those, most patients suffered from grade 4 brain tumors (67%), followed by grade 2 (22%) and grade 1 (11 %) tumors. Mean muscle strength increased in all muscle groups tested (knee extension +13.5%, p=.024, CI 95%: -0.5 - 29.1; knee flexion +7.1%, p=.048 CI 95%: -1.0 - 14.0; adductors +6.6%, p=.039, CI 95%: 1.3 - 13.4; abductors 20.0%, p=.004, CI 95%: 6.9 - 35.7; leg press +19.5%, p=.050, CI 95%: -5.6 - 44.6). Tumor grade, gender, type of ski intervention, and age did not affect the RESULTS . CONCLUSION During one week of intensive ski training, positive effects on leg muscle strength could be shown in both brain tumor patients and their families regardless of age, gender, downhill/cross-country ski, or WHO grading. Furthermore, this study demonstrates feasibility and safety of ski-based exercises in this patient population. Interventions such as these could help patients overcome (gait) insecurities and motivate them to become more physically active in their daily lives. In the longer term, this may lead to better management of everyday life and improved quality of life.
P17.10.B VOLUMETRIC DIFFERENCES IN TARGET DEFINITON OF RECURRENT HIGH-GRADE GLIOMAS USING CONTRAST ENHANCED MRI VS.[18F] FDOPA PET IN RADIOSURGICAL PLANNING
Authors: N Obad, Ø Tveiten, M Biermann, J Brekke
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Radiosurgical treatment of high-grade gliomas usually bases target definition on contrast-enhanced T1-weighted MRI images. Despite advances in several MRI techniques, a number of limitations exist, primarily due to the disruption of the blood-brain barrier, making the target delineation less accurate, particularly when treating recurrences. Several studies support the use of amino acid PET/MRI in distinguishing progression from post-operative/post-radiation inflammation. However, no established guidelines define the biological target volume when using amino acid PET/MRI in radiosurgical treatment planning. We aimed to explore the volumetric differences in target volumes obtained with standard contrast-enhanced MRI versus [18F]FDOPA PET in patients with recurrent high-grade gliomas (rHGG). MATERIAL AND METHODS Ten patients obtained [18F]FDOPA PET/MRI within 1 week before radiosurgical treatment. We co-registered these images with the 3D MPRAGE-MRI typically used for stereotactic target definition and performed a follow-up PET/MRI scan 4-6 weeks after treatment. We reviewed and compared the method of tumor delineation, target volumes, and stereotactic accuracy in both modalities. RESULTS Radiosurgical treatment delivers high radiation doses to defined targets. The target volume and the proximity to eloquent structures limit the dose, thus depending on high-accuracy imaging. The invasive nature of malignant brain tumors makes anatomical delineation insufficient, particularly when treating recurrences. In such cases, amino acid PET supplies additional information. However, the spatial resolution afforded by [18F]FDOPA uptake alone is insufficient for stereotactic definition, which to a large degree is based on contrast-enhanced T1-weighted MRI images in order to achieve the sub-millimeter resolution needed for radiosurgical planning. Hybrid PET/MRI allows the combination of metabolic information of [18F]FDOPA-PET with the anatomical precision of stereotactic MRI. In the recurrent setting, [18F]FDOPA-PET supplies the necessary information for targeting the biologically active tumour, differentiating it from radiation necrosis, thus limiting the target volumes. This enables us to treat the recurrent tumours more efficiently. CONCLUSION [18F]FDOPA-PET is a useful supplement in radiosurgical planning and treatment of rHGG. It is helpful in the delineation of the biologically active tumor, thus limiting the target volume significantly. This enables higher radiation doses and potentially more efficient treatment. Further results will be presented.
P11.82.A TARGETING THE GLIOBLASTOMA MASTER REGULATOR C/EBPß: A PHARMACOKINETIC AND PHARMACODYNAMIC NEOADJUVANT STUDY OF ST101
Authors: F Iwamoto, O Al Dalahmah, K Manjrekar, C Levrero, R Michel, A Bargo, S Kaesshaefer, N Butowski, K Peters, R Buerki, A Bexon, A Vainstein-Haras
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The vast amounts of genomics, epigenomics and transcriptomics data in glioblastoma (GBM) have yet to translate into better outcomes to most patients. One of the main challenges is to how to best integrate these diverse layers of omics to personalize and improve the treatment of glioblastomas. Cancer master regulators are often transcription factors (TFs), which control the expression of many genes and considered promising antitumor targets. CCAAT/enhancer-binding protein β (C/EBPβ) is an abundantly-expressed transcription factor (Zahnow 2009). C/EBPβ was previously described as a master regulator in GBM (Carro 2010). ST101 is a first-in-class cell-penetrating peptide antagonist of C/EBPβ with known ability to cross the blood-brain barrier. We have demonstrated potent anti-tumor activity with ST101 in multiple in vivo models including glioblastoma. Based on early efficacy data on the initial clinical study including objective responses in GBM, we designed this surgical study to further understand the antitumor mechanisms of ST101. METHODS we will recruit total of 12 newly diagnosed GBM and 6 recurrent patients. Recurrent GBM patients who are deemed surgical candidates will be treated with ST101 at the RP2D of 500 mg IV weekly for 2 to 4 weeks and then undergo standard of care surgical resection. After recovery from surgery, patients will continue ST101 until there is significant toxicity or tumor progression. 12 patients with newly diagnosed GBM who had undergone a prior biopsy or partial resection, and that upon further neurosurgical evaluation have an indication for additional debulking surgery will be eligible for this study. Patients will be treated with ST101 at the recommended phase 2 dose for 2 weeks and then undergo standard of care surgical resection. Patients will undergo standard of care treatment with radiation and temozolomide and continue ST101 after recovery from surgery. ST101 plasma concentration will be correlated with ST101 drug levels in enhancing and non-enhancing tumor tissue of recurrent and newly diagnosed patients. We will compare the molecular abnormalities in the post-treatment tissue through deep bulk whole-exome sequencing and mRNAseq against the intra-patient baseline tissue. Pharmacodynamics evaluation will focus on the expression of genes regulated by the transcription factor CEBPβ, such as BCL2, cyclins and cyclin-dependent kinases and inhibition of differentiation genes. Due to the diversity of cell types in the tumor microenvironment and the early data that ST101 can also reprogram M2 macrophages to M1 in addition to its direct antitumor effects, we will perform single nucleus RNAseq on these surgical specimens. Enrollment has started in January 2023 and 6 recurrent and 2 newly diagnosed patients have been accrued.
P04.08.A PATIENT-DERIVED ORGANOIDS FOR MODELING AND CHARACTERIZING PEDIATRIC BRAIN TUMORS
Authors: C Lago, A Federico, G Leva, C Ballabio, M Gianesello, L Abballe, M Kool, E Miele, L Tiberi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Central nervous system (CNS) tumors are the most common solid tumors in the pediatric population and the leading cause of death among childhood cancers. They present common features related to the development and produce symptoms based on their location, rate of tumor growth and age of the child. Tumors of embryonal origin, such as medulloblastoma or primitive neuroectodermal tumor, have a higher incidence in younger patients, whereas older ones tend to present tumors of glial origin. Most of CNS-embryonal tumors are highly malignant and consequently leading to poor prognoses. Despite the understanding of their underlying molecular landscape that has helped in clinical advances to improve life expectancies of the patients, there is still an emerging need to minimize morbidity and manage the long-term therapy effects. MATERIAL AND METHODS Human samples were collected according to protocols approved by the institutional review board with written consent. Patient-Derived Organoids (PDOs) and Patient-Derived Xenograft Organoids (PDXOs) were obtained using scalpels by chopping in small pieces the tumor tissue and were grown in PDOs medium. PDOs and PDXOs were analyzed through DNA methylation, immunostainings, sc-RNA sequencing and orthotopic nude mice engraftment. Therapeutic regimens were adapted according to patients’ treatment protocols depending on the tumor of origin. RESULTS Developing new models to better understand the complexity and heterogeneity of pediatric tumors and to test personalized treatment strategies remains a clinical challenge. We tried to answer this medical need with PDOs and PDXOs established through the direct in vitro culture of different kinds of primary tumors (ependymoma EPN, medulloblastoma MB and low-grade glial tumors) and MB patient derived xenograft (PDX)-derived tumors. We have developed a method that recapitulates mutational profiles, histological features, and cellular heterogeneity of the corresponding parental tumors. We have obtained promising results from the DNA methylation profile analysis, nowadays used for an accurate routine CNS tumors diagnosis. Through this new model, we confirmed the action of clinically used therapeutic regimens, i.e., for EPN with ZFTA-RELA fusion and G3 MB-derived PDOs. PDOs were subjected to the same treatment the patients underwent and responded similarly to the patients. CONCLUSION We found a suitable in vitro culture condition to generate and maintain PDOs from different kinds of pediatric brain tumors. Their reliability has been proved by different analyses, confirming they still resemble the parental tumors. Through this new model, we confirmed the action of clinically used therapeutic regimens, suggesting its potential at the translation level as a reliable tool for testing personalized medicine, drug screening and development of newer and more specific therapeutic strategies.